Skip to main content
Springer Nature Link
Log in

The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure

  • Research Papers
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Summary

A new simple empirical function has been developed that estimates the free energy of binding for a given protein-ligand complex of known 3D structure. The function takes into account hydrogen bonds, ionic interactions, the lipophilic protein-ligand contact surface and the number of rotatable bonds in the ligand. The dataset for the calibration of the function consists of 45 protein-ligand complexes. The new energy function reproduces the binding constants (ranging from 2.5·10-2 to 4·10-14 M, corresponding to binding energies between -9 and -76 kJ/mol) of the dataset with a standard deviation of 7.9 kJ/mol, corresponding to 1.4 orders of magnitude in binding affinity. The individual contributions to protein-ligand binding obtained from the scoring function are: ideal neutral hydrogen bond: -4.7 kJ/mol; ideal ionic interaction: -8.3 kJ/mol; lipophilic contact: -0.17 kJ/mol Å2; one rotatable bond in the ligand: +1.4 kJ/mol. The function also contains a constant contribution (+5.4 kJ/mol) which may be rationalized as loss of translational and rotational entropy. The function can be evaluated very fast and is therefore also suitable for application in a 3D database search or de novo ligand design program such as LUDI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.

    Google Scholar 

  2. Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.

    Google Scholar 

  3. Meng, E.C., Shoichet, B.K. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 505.

    Google Scholar 

  4. Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.

    Google Scholar 

  5. Tomioka, N., Itai, A. and Iitaka, Y., J. Comput.-Aided Mol. Design, 1 (1987) 197.

    Google Scholar 

  6. Moon, J.B. and Howe, W.J., Proteins, 11 (1991) 314.

    Google Scholar 

  7. Goodford, P.J., J. Med. Chem., 28 (1985) 849.

    Google Scholar 

  8. Boobyer, D.N.A., Goodford, P.J., McWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.

    Google Scholar 

  9. Williams, D.H., Cox, J.P.L., Doig, A.J., Gardner, M., Gerhard, U., Kaye, P.T., Lal, A.R., Nicholls, I.A., Salter, C.J. and Mitchell, R.C., J. Am. Chem. Soc., 113 (1991) 7020.

    Google Scholar 

  10. Williams, D.H., Searle, M.S., Mackay, J.P., Gerhard, U. and Maplestone, R.A., Proc. Natl. Acad. Sci. USA, 90 (1993) 1172.

    Google Scholar 

  11. Searle, M.S. and Williams, D.H., J. Am. Chem. Soc., 114 (1992) 10690.

    Google Scholar 

  12. Horton, N. and Lewis, M., Protein Sci., 1 (1992) 169.

    Google Scholar 

  13. Bohacek, R.S. and McMartin, C., J. Med. Chem., 35 (1992) 1671.

    Google Scholar 

  14. Connolly, M.L., Science, 221 (1983) 458.

    Google Scholar 

  15. Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., MeyerJr., E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, T., J. Mol. Biol., 112 (1977) 535.

    Google Scholar 

  16. Mares-Guia, M. and Shaw, E., J. Biol. Chem., 240 (1965) 1579.

    Google Scholar 

  17. Bode, W., Turk, D. and Stürzebecher, J., Eur. J. Biochem., 193 (1990) 175.

    Google Scholar 

  18. Kikumoto, R., Tamao, Y., Tezuka, T., Tonomura, S., Hara, H., Ninomiya, K., Hijikata, A. and Okamoto, S., Biochemistry, 23 (1984) 85.

    Google Scholar 

  19. Stürzebecher, J., Walsmann, P., Voigt, B. and Wagner, G., Thromb. Res., 36 (1984) 457.

    Google Scholar 

  20. Gubernator, K., private communication, 1993.

  21. Wallace, R.A., Kurtz, A.N. and Niemann, C., Biochemistry, 2 (1963) 824.

    Google Scholar 

  22. Matthews, B.W., Acc. Chem. Res., 21 (1988) 333.

    Google Scholar 

  23. Rahuel, J., Priestle, J.P. and Grütter, M.G., J. Struct. Biol., 107 (1991) 227.

    Google Scholar 

  24. Cooper, J., Foundling, S., Hemmings, A. and Blundell, T., Eur. J. Biochem., 169 (1987) 215.

    Google Scholar 

  25. Zollner, H., Handbook of Enzyme Inhibitors, VCH Publishers, Weinheim, 1993.

    Google Scholar 

  26. Blundell, T.L., Cooper, J., Foundling, S.I., Jones, D.M., Atrash, B. and Szelke, M., Biochemistry, 26 (1987) 5585.

    Google Scholar 

  27. Erickson, J., Neidhart, D.J., VanDrie, J., Kempf, D.J., Wang, X.C., Norbeck, D.W., Plattner, J.J., Rittenhouse, J.W., Turon, M., Wideburg, N., Kohlbrenner, W.E., Simmer, R., Helfrich, R., Paul, D.A. and Knigge, M., Science, 249 (1990) 527.

    Google Scholar 

  28. Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.

    Google Scholar 

  29. Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, S., Science, 246 (1989) 1149.

    Google Scholar 

  30. Bolin, J.T., Filman, D.A., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.

    Google Scholar 

  31. Blaney, J.M., Hansch, C., Silipo, C. and Villon, A., Chem. Rev., 84 (1984) 333.

    Google Scholar 

  32. Appelt, K., Bacquet, R.J., Bartlett, C.A., Booth, C.L.J., Freer, S.T., Fuhry, M.A.M., Gehring, M.R., Herrmann, S.M., Howland, E.F., Janson, C.A., Jones, T.R., Kan, C.-C., Kathardekar, V., Lewis, K.K., Marzoni, G.P., Matthews, D.A., Mohr, C., Moomaw, E.W., Morse, C.A., Oatley, S.J., Ogden, R.C., Reddy, M.R., Reich, S.H., Schoettlin, W.S., Smith, W.W., Varney, M.D., Villafranca, J.E., Ward, R.W., Webber, S., Webber, S.E., Welsh, K.M. and White, J., J. Med. Chem., 34 (1991) 1834.

    Google Scholar 

  33. Weber, P.C., Wendoloski, J.J., Pantoliano, M.W. and Salemme, F.R., J. Am. Chem. Soc., 114 (1992) 3197.

    Google Scholar 

  34. Cowan, S.W., Newcomer, M.E. and Jones, T.A., Proteins, 8 (1990) 44.

    Google Scholar 

  35. Lowe, J.B., Sacchettini, J.C., Laposata, M., McQuillan, J.J. and Gordon, J.I., J. Biol. Chem., 262 (1987) 5931.

    Google Scholar 

  36. Miller, D.M., Olson, J.S., Pflugrath, J.W. and Quiocho, F.A., J. Biol. Chem., 258 (1983) 13665.

    Google Scholar 

  37. Van, Duyne, G.D., Standaert, R.F., Karplus, P.A., Schreiber, S.L. and Clardy, J., Science, 252 (1991) 839.

    Google Scholar 

  38. Badger, J., Minor, I., Kremer, M.J., Oliveira, M.O., Smith, T.J., Griffith, J.P., Guerin, D.M.A., Krishnaswamy, S., Luo, M., Rossmann, M.G., McKinlay, M.A., Diana, G.D., Dutko, F.J., Fancher, M., Rueckert, R.R. and Heinz, B.A., Proc. Natl. Acad. Sci. USA, 85 (1988) 3304.

    Google Scholar 

  39. Entsch, B., Ballou, D.P. and Massey, V., J. Biol. Chem., 251 (1976) 2550.

    Google Scholar 

  40. Dani, M., Manca, F. and Rialdi, G., Biochim. Biophys. Acta, 667 (1981) 108.

    Google Scholar 

  41. Bolognesi, M., Cannilo, E., Ascenzi, P., Giacometti, G.M., Merli, A. and Brunori, M., J. Mol. Biol., 158 (1982) 305.

    Google Scholar 

  42. Sauter, N.K., Bednarski, M.D., Wurzburg, B.A., Hanson, J.E., Whitesides, G.M., Skehel, J.J. and Wiley, D.C., Biochemistry, 28 (1989) 8388.

    Google Scholar 

  43. Bunting, J.W. and Myer, C.D., Can. J. Chem., 53 (1975) 1993.

    Google Scholar 

  44. Kim, H. and Lipscomb, W.N., Biochemistry, 29 (1990) 5546.

    Google Scholar 

  45. Brandstetter, H., Turk, D., Hoeffken, H.W., Grosse, D., Stürzebecher, J., Martin, P.D., Edwards, B.F.P. and Bode, W., J. Mol. Biol., 226 (1992) 1085.

    Google Scholar 

  46. Roderick, S.L., Fournie-Zuliski, M.C., Roques, B.P. and Matthews, B.W., Biochemistry, 28 (1989) 1493.

    Google Scholar 

  47. Program INSIGHT, Biosym Technologies, Inc., San Diego, CA, 1993.

  48. Turk, D., Stürzebecher, J. and Bode, W., FEBS Lett., 287 (1991) 133.

    Google Scholar 

  49. Lipscomb, J.D., Biochemistry, 19 (1980) 3590.

    Google Scholar 

  50. Fisher, M.T. and Sligar, S.G., J. Am. Chem. Soc., 107 (1985) 5018.

    Google Scholar 

  51. Kim, H. and Lipscomb, W.N., Biochemistry, 30 (1991) 8171.

    Google Scholar 

  52. Selassie, C.D., Fang, Z.X., Li, R.L., Hansch, C., Debnath, G., Klein, T.E., Langridge, R. and Kaufman, B.T., J. Med. Chem., 32 (1989) 1895.

    Google Scholar 

  53. Roth, B. and Stammers, D.K., In Bedell, C.R. (Ed.) The Design of Drugs to Macromolecular Targets, Wiley, New York, NY, 1992, pp. 85–118.

    Google Scholar 

  54. Dauber-Osguthorpe, P., Roberts, V.A., Osguthorpe, D.J., Wolff, J., Genest, M. and Hagler, A.T., Proteins, 4 (1988) 31.

    Google Scholar 

  55. Fersht, A.R., Shi, J.P., Knill-Jones, J., Lowe, D.M., Wilkinson, A.J., Blow, D.M., Brick, P., Carter, P., Waye, M.M.Y. and Winter, G., Nature, 314 (1985) 235.

    Google Scholar 

  56. Shirley, B.A., Stanssens, P., Hahn, U. and Pace, C.N., Biochemistry, 31 (1992) 725.

    Google Scholar 

  57. Richards, F.M., Annu. Rev. Biophys. Bioeng., 6 (1977) 151.

    Google Scholar 

  58. Sharp, K.A., Nicholls, A., Friedman, R. and Honig, B., Biochemistry, 30 (1991) 9686.

    Google Scholar 

  59. Hoffmann, R.W., Angew. Chem., 104 (1992) 1147.

    Google Scholar 

  60. Lim, M.S.L., Johnston, E.R. and Kettner, C.A., J. Med. Chem., 36 (1993) 1831.

    Google Scholar 

  61. Andrews, P.R., Craik, D.J. and Martin, J.L., J. Med. Chem., 27 (1984) 1648.

    Google Scholar 

  62. Page, M.I., Angew. Chem., Int. Ed. Engl., 16 (1977) 49.

    Google Scholar 

  63. Jorgensen, W.L., Nguyen, T.B., Sanford, E.M., Chao, I., Houk, K.N. and Diederich, F., J. Am. Chem. Soc., 114 (1992) 4003.

    Google Scholar 

  64. Inoue, Y., Hakshi, T., Liu, Y., Tong, L.H., Shen, B.J. and Jin, D.S., J. Am. Chem. Soc., 115 (1993) 475.

    Google Scholar 

  65. Eriksson, A.E., Baase, W.A., Wozniak, J.A. and Matthews, B.W., Nature, 355 (1992) 371.

    Google Scholar 

  66. Dao-Pin, S., Nicholson, H., Baase, W.A., Zhang, X.-J., Wozniak, J.A. and Matthews, B.W., In Chadwich, D.J. (Ed.) Protein Conformation, Ciba Foundation Symposium, Vol. 161, Wiley, Chichester, 1991, pp. 52–62.

    Google Scholar 

  67. Morgan, B.P., Scholtz, J.M., Ballinger, M.D., Zipkin, I.D. and Bartlett, P.A., J. Am. Chem. Soc., 113 (1991) 297.

    Google Scholar 

  68. Dougherty, D.A. and Stauffer, D.A., Science, 250 (1990) 1558.

    Google Scholar 

  69. Baker, B.R. and Erickson, E.H., J. Med. Chem., 10 (1967) 1123.

    Google Scholar 

  70. Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.

    Google Scholar 

  71. LUDI is available from Biosym Technologies, Inc., San Diego, CA.

Download references

Author information

Authors and Affiliations

  1. Central Research, BASF AG, D-67056, Ludwigshafen, Germany

    Hans-Joachim Böhm

Authors
  1. Hans-Joachim Böhm
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Böhm, HJ. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Computer-Aided Mol Des 8, 243–256 (1994). https://doi.org/10.1007/BF00126743

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00126743

Key words